Substituted 2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid, compositions and use

ABSTRACT

Substituted 2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid derivatives and methods for their preparation and use are disclosed. The compounds are useful analgesic and antiinflammatory agents.

BACKGROUND OF THE INVENTION

a. Field of Invention

This invention relates to tricyclic acetic acid derivatives, to theirpreparation and use, and to intermediates used for their preparation.

More specifically, this invention relates to tricyclic acetic acidderivatives in which the tricyclic portion thereof is characterized byhaving an indole portion fused to a cyclohexane ring. Still morespecifically, the compounds of this invention are characterized asderivatives of the following tricyclic acetic acid system: ##STR1##2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid in which the carbons atthe 1-, 4- and 8-positions are further substituted.

The tricyclic acetic acid compounds of this invention possess usefulpharmacologic properties; for instance, they exhibit analgesic andantiinflammatory activity at dose levels which do not elicit undesirableside effects. The foregoing combination of attributes renders thecompounds of this invention useful for the treatment of inflammatory orpainful conditions in a mammal.

b. Prior Art

The closest prior art to the present invention is:

Mobilio et al. U.S. application Ser. No. 726,197 and Asselin et al. U.S.application Ser. No. 740,123. U.S. Pat. No. 4,057,559. Mobilio et al.and Asselin et al. disclose analgesic and antiinflammatory agents havingthe same heterocyclic ring system as the present invention but withoutthe 1-, 4- and 8-substituents of the present invention.

Demerson et al. U.S. Pat. No. 3,939,178 discloses1,3,4,9-tetrahydropyrano[3,4-b]indoles and1,3,4,9-tetrahydrothiopyrano[3,4-b]indoles having analgesic andantiinflammatory activity. Related U.S. patents are U.S. Pat. Nos.3,974,179 and 3,843,681.

Boehringer Mannheim European Patent No. 42593 generically disclosesstarting materials useful for producing cardiotonic and beta-blockingagents. The starting materials include 1,2,3,4-tetrahydrocarbazoles withsubstituents selected from the broad group including hydrogen, carboxy,lower alkyl and lower alkenyl. The starting materials are in each casealso substituted with a reactive group which distinguishes them from thecompounds of the present invention.

Further removed, related patents that include tetrahydrocarbazoleaceticacid derivatives useful as analgesic and antiinflammatory agents areU.S. Pat. Nos. 4,234,487; 4,264,500; 4,193,923; 4,158,007; 4,146,542;3,896,145 and 3,824,314; Japanese Patent No. J51032556; NetherlandPatent NL No. 7,100,213 and Great Britain Patent GB No. 1385620.

SUMMARY OF THE INVENTION

The compounds of this invention are represented by formula (I) ##STR2##wherein R¹ is lower alkyl, R², R³ and R⁴ are hydrogen or lower alkyl orR² and R⁴ are joined together to give

    --CH═CH--CH═CH--

and form a benzene ring, R⁵ is hydrogen, lower alkyl or halogen, and thepharmaceutically acceptable salts thereof.

A preferred aspect of the present invention are the compoundsrepresented by formula (I), wherein R¹ is lower alkyl containing 1 to 6carbon atoms, R², R³ and R⁴ are independently hydrogen or lower alkylcontaining 1 to 6 carbon atoms or R² and R⁴ are joined together to give

    --CH═CH--CH═CH--

and form a benzene ring, R⁵ is hydrogen, lower alkyl containing 1 to 6carbon atoms or halogen, and the pharmaceutically acceptable saltsthereof.

A still further preferred aspect of the present invention are thecompounds represented by formula (I), wherein R¹ is ethyl, R², R³ and R⁴are hydrogen or R² and R⁴ are joined together to give

    --CH═CH--CH═CH--

and form a benzene ring, R⁵ is hydrogen or ethyl, and thepharmaceutically acceptable salts thereof.

The most preferred compounds of the present invention are designated4-ethenyl-1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid,1,8-diethyl-2,3,4,9-tetrahydro-4-phenyl-1H-carbazole-1-acetic acid and4-(1-methylethenyl)-1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-aceticacid.

The compounds of the present invention are prepared by a process inwhich the unsaturated ketone of structure (IV) ##STR3## wherein R¹ is asdefined above and R⁶ is lower alkyl is reacted in the presence of asuitable copper catalyst selected from the group consisting of copperbromide dimethyl sulfide complex, cuprous iodide, cuprous bromide,copper acetate, cuprous chloride and tributylphosphine cuprous iodidecomplex, with the organometallic reagent ##STR4## wherein R², R³ and R⁴are as defined above and M may be MgBr, MgCl or MgI to obtain a compoundof structures (V) ##STR5## wherein R¹, R², R³, R⁴ and R⁶ are as definedabove and further reacting a compound of structure (V) with thesubstituted hydrazine of formula (VI) ##STR6## wherein R⁵ is as definedabove to obtain the corresponding hydrazone of structure (VII) ##STR7##wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined above. The hydrazone istreated with a cyclizing agent to give the ester of compound (I) andafter hydrolyzing acid ester compound (I) is obtained.

DETAILED DESCRIPTION OF THE INVENTION

The term "lower alkyl" as used herein contemplates straight chain alkylradicals containing from one to six carbon atoms and branched chainalkyl radicals containing from three to four carbon atoms and includesmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and thelike.

The term "halogen" as used herein includes fluorine, chlorine, bromineand iodine.

The compounds of formula (I) form salts with suitable pharmaceuticallyacceptable inorganic and organic bases. These derived salts possess thesame activity as the parent acid and are included within the scope ofthis invention. The acid of formula (I) is transformed in excellentyield into the corresponding pharmaceutically acceptable salts byneutralization of said acid with the appropriate inorganic or organicbase. The salts are administered in the same manner as the parent acidcompounds. Suitable inorganic bases to form these salts include, forexample, the hydroxides, carbonates, bicarbonates or alkoxides of thealkali metals or alkaline earth metals, for example, sodium, potassium,magnesium, calcium and the like. Suitable organic bases include thefollowing amines; lower mono-, di- and tri-alkylamines, the alkylradicals of which contain up to three carbon atoms, such as methylamine,dimethylamine, trimethylamine, ethylamine, di- and triethylamine,methylethylamine, and the like; mono, di- and trialkanolamines, thealkanol radicals of which contain up to three carbon atoms, such asmono-, di- and triethanolamine; alkylenediamines which contain up to sixcarbon atoms, such as hexamethylenediamine; cyclic saturated orunsaturated bases containing up to six carbon atoms, such aspyrrolidine, piperidine, morpholine, piperazine and their N-alkyl andN-hydroxyalkyl derivatives, such as N-methylmorpholine andN-(2-hydroxyethyl)piperidine, as well as pyridine. Furthermore, theremay be mentioned the corresponding quaternary salts, such as thetetraalkyl (for example tetramethyl), alkyl-alkanol (for examplemethyltrimethanol and trimethyl-monoethanol) and cyclic ammonium salts,for example the N-methyl-pyridinium,N-methyl-N-(2-hydroxyethyl)-morpholinium, N,N-dimethyl-morpholinium,N-methyl-N-(2-hydroxyethyl)-morpholinium, N,N-dimethylpiperidiniumsalts, which are characterized by good water-solubility. In principle,however, there can be used all the ammonium salts which arephysiologically compatible.

The transformations to the salts can be carried out by a variety ofmethods known in the art. For example, in the case of the inorganicsalts, it is preferred to dissolve the acid of formula (I) in watercontaining at least one equivalent amount of a hydroxide, carbonate, orbicarbonate corresponding to the inorganic salt desired. Advantageously,the reaction is performed in a water-miscible organic solvent inert tothe reaction conditions, for example, methanol, ethanol, dioxane, andthe like in the presence of water. For example, such use of sodiumhydroxide, sodium carbonate or sodium bicarbonate gives a solution ofthe sodium salt. Evaporation of the solution or addition of awater-miscible solvent of a more moderate polarity, for example, a loweralkanol, for instance, butanol, or a lower alkanone, for instance, ethylmethyl ketone, gives the solid inorganic salt if that form is desired.

To produce an amine salt, the acid of formula (I) is dissolved in asuitable solvent of either moderate or low polarity, for example,ethanol, acetone, ethyl acetate, diethyl ether and benzene. At least anequivalent amount of the amine corresponding to the desired cation isthen added to that solution. If the resulting salt does not precipitate,it can usually be obtained in solid form by addition of a misciblediluent of low polarity, for example, benzene or petroleum ether, or byevaporation. If the amine is relatively volatile, any excess can easilybe removed by evaporation. It is preferred to use substantiallyequivalent amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe acid of formula (I) with an equivalent amount of the correspondingquaternary ammonium hydroxide in water solution, followed by evaporationof the water.

Included in the present invention are the diastereo isomers wherein the4-substituent is either cis or trans to the acetic acid chain atposition one.

Also included in this invention are the optical isomers of the compoundsof formula (I) which result from asymmetric centers, contained therein.Such isomers are obtained in substantially pure form by classicalseparation techniques and by sterically controlled synthesis.

Antiinflammatory Activity

The useful antiinflammatory activities of the tricyclic acetic acidderivatives of formula (I) are demonstrated in standard pharmacologictests, for example, the test designated: PREVENTATIVE ADJUVANT EDEMA.

The objective of this test is to determine the ability of test drugs toexhibit an acute anti-inflammatory effect in rats. This test is aprimary screen for anti-inflammatory drugs.

Species:

Male Sprague Dawley rats (180-200 g) are used. The animals have freeaccess water but food is withdrawn 18 hours before testing.

Drug Preparations and Administration:

Freund's complete adjuvant is prepared by suspending 5 mg killed anddried Mycobacterium butyricum (Difco) in 1 ml liquid paraffin. The testcompounds are dissolved in distilled water or suspended in distilledwater with a few drops of Tween 80 according to their solubility. Forprimary screening all drugs are administered by gastric lavage at thearbitrary dosage of 100 mg/kg, p.o. in a volume of 0.5 ml/100 g bodyweight to groups of 10 animals.

Methodological Details:

The method is essentially that described by Wax et al., J. Pharmacol.Exp. Ther., 192, 166-171 (1975). Groups of rats are injectedintradermally in the left hind paw with 0.1 ml of Freund's completeadjuvant. The test compound or vehicle is administered immediatelybefore the adjuvant, 24 hours and 48 hours after the adjuvant (day 0, 1and 2). The injected hind paw volume is measured before the injection ofadjuvant and 24 hrs. after the last drug administration (day 3) by meansof a plethysmometer (Buxco Electronics Inc.). The difference between thehind paw volume on day 0 and day 3 represents the edema volume.Phenylbutazone (50 mg./kg, p.o.) is included as a positive control.

Presentation of Results:

The mean edema volume (expressed as ml±SEM) is calculated for each groupand the percentage protection conferred by the drug is calculated:##EQU1## where c is the mean edema volume for the untreated controls andt is the mean edema volume for the drug treated group.

A further test used to determine the utility of the compounds of thepresent invention is designated: DRUG EFFECTS IN PHENYLQUINONE-INDUCEDWRITHING IN MICE.

The objective of this test is to determine the ability of test drugs toinhibit the nociceptive (pain) response of mice injected with a chemicalirritant. This test is a primary screen for both peripheral andcentrally acting analgesic drugs.

Species:

Male Swiss albino mice (15-25 g). The animals are fasted for 18 hoursprior to use but have free access to water.

Drug Preparation and Administration:

Drugs are dissolved or suspended according to their solubility in 0.5%methyl cellulose or 0.5% Tween 80. They are administered by gastriclavage in a volume of 5 ml/kg. For primary screening all drugs areadministered at the arbitrary dosage of 200 mg/kg, p.o. to a group of 10mice.

Methodological Details:

A modification of the method of Siegmund et al., Proc. Soc. Exp. Biol.Med., 95, 729-731 (1957) is used. Groups of 5 mice are dosed with thetest compound or vehicle control. Sixty minutes later the animals areinjected i.p. with 0.3 ml/20 g body weight of a 0.02% solution ofphenylquinone (PBQ; 2-phenyl-1,4-benzoquinone) and placed in individualobservation boxes. The number of writhing or abdominal squirmingmovements made by each mouse during the following 15 min. period iscounted. The experiment is repeated with another group of 5 mice and themean number of writhes per mouse for a group of 10 mice is calculated.

Presentation of Results:

Drug treated and vehicle-treated control groups are compared and thepercentage protection conferred by the drug is calculated: ##EQU2##where c=mean number of writhes in the control group where t=mean numberof writhes in the test drug group

Typical results obtained for the compounds of the present invention inthe aforementioned tests are as follows:

    ______________________________________                                        Preventative Adjuvant Edema                                                                 Dose                                                            Compound      (mg/kg, p.o.)                                                                            % Inhibition                                         ______________________________________                                        Example 1 h   25         62                                                   Example 1 g   25         30                                                   Example 2 e   25         37                                                   Example 2 d   25         12                                                   Example 3 d   50         25                                                   Example 3 e   25         46                                                   ______________________________________                                    

    ______________________________________                                        Phenylquinone Writhing in Mice                                                              Dose                                                            Compound      (mg/kg, p.o.)                                                                            % Inhibition                                         ______________________________________                                        Example 1 h   25          0                                                   Example 1 g   25         21                                                   Example 2 e   25         28                                                   Example 2 d   25         17                                                   Example 3 d   200        50                                                   Example 3 e   25          0                                                   ______________________________________                                    

The lack of side effects for the compounds of this invention aredemonstrated by standard acute toxicity tests described by R. A. Turnerin "Screening Methods in Pharmacology," Academic Press, New York andLondon, 1965, pp. 152-163 and by prolonged administration of thecompound to warm-blooded animals.

When the compounds of this invention are employed as antiinflammatoryand analgesic agents in warm-blooded animals, they are administeredorally, alone or in dosage forms, i.e., capsules or tablets, combinedwith pharmacologically acceptable excipients, such as starch, milk sugarand so forth, or they are administered orally in the form of solutionsin suitable vehicles such as vegetable oils or water. The compounds ofthis invention may be administered orally in sustained release dosageform or transdermally in ointments or patches. The compounds of thisinvention may also be administered in the form of suppositories.

The dosage of the compounds of formula I of this invention will varywith the particular compound chosen and form of administration.Furthermore, it will vary with the particular host under treatment.Generally, the compounds of this invention are administered at aconcentration level that affords protective effects without anydeleterious side effects. These antiinflammatorily effectiveconcentration levels are usually obtained within a therapeutic range of1.0 μg to 500 mg/kg per day, with a preferred range of 10 μg to 100mg/kg per day.

The compounds of this invention also possess antipyretic activity.

The compounds of this invention may be administered together with theusual doses of caffeine.

The preferred process for obtaining the compounds of the presentinvention is exemplified by the process for obtaining4-substituted-1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-acetic acids(XII) outlined in Scheme 1. ##STR8##

In Scheme 1, Step 1, 2-ethylcyclohexanone (VIII) was alkylated withmethyl bromoacetate according to the procedure of E. Negishi et al. Tet.Lett. 24, 1341 (1983) in the presence of potassium hydride, andtriethylborane in tetrahydrofuran. This afforded2-carbomethoxymethyl-2-ethylcyclohexanone (IX) in 45% yield. Compound(IX) was previously reported in Asselin et al., J. Med. Chem., 19, 787(1976). About 5-10% of the 2,6 regioisomer was also formed which wasseparated by flash chromatography.

Conversion of (IX) to2-phenylseleno-6-carbomethoxymethyl-6-ethylcyclohexanone withphenylselenenyl chloride according to the procedure of K. B. Sharplesset al., J. Amer. Chem. Soc. 95, 6137 (1973) and oxidative eliminationwith hydrogen peroxide in Step 2 led to the required enone (X) in 55-68%yield in a one pot conversion.

Conjugate addition of organometallic reagents RM to (X) in Step 3wherein R is CH═CH₂, phenyl, or C(CH₃)═CH₂ and M is MgBr gavetrisubstituted ketones (XI) as a mixture of diastereomers. Fischerindole cyclization with 2-ethylphenylhydrazine in Step 4 and subsequentbase hydrolysis in Step 5 gave tetrahydrocarbazoles (XII). Thediastereomers, which represent another aspect of the invention, can beseparated either before or after cyclization.

Conjugate addition reactions of organometallic reagents RM to (X) inStep 3 gave about a 1:1 to a 2:1 mixture of diastereomers (XI) whencarried out

                  TABLE 1                                                         ______________________________________                                         ##STR9##                                                                                                         Ratio of                                  Entry RM             % of Yield of (XI)                                                                           Isomers                                   ______________________________________                                        1     CH.sub.2CHMgBr 69             56:44                                     2     PhMgBr         71             1:1                                       3     CH.sub.2C(CH.sub.3)MgBr                                                                      71             --                                        ______________________________________                                    

at -40° C. in tetrahydrofuran (THF) by adding an ether or THF solutionof the Grignard reagent (1 to 1.4 equivalents) to a solution of (X) inTHF/Me₂ S containing 0.1 equivalents of copper bromide dimethyl sulfidecomplex [(K. J. Shea et al. Tetrahedron Lett., 24, 1003 (1983)]. SeeTable 1, Entry 1.

The ketones (XI) were then subjected to Fischer indole synthesisconditions in Step 4 by refluxing with 2-ethylphenylhydrazine inmethanol the appropriate time to form the hydrazones (See Table 2). Thehydrazone solution was then cooled to 0° C., treated with acetylchloride to generate HCl and refluxed an additional 45 minutes to affectFischer indole cyclization. The esters were then hydrolyzed in Step 5with potassium carbonate in aqueous methanol to affordtetrahydro-1-H-carbazole-1-acetic acids (XII).

                  TABLE 2                                                         ______________________________________                                                  hours                                                                         for hydrazone                                                                            %           %                                            R         formation  yield of ester*                                                                           yield of (XII)*                              ______________________________________                                        CH.sub.2 ═CH                                                                        48         38(26)      65(91)                                       phenyl    48         32(27)      100(100)                                     CH.sub.2 ═C(CH.sub.3)                                                               144        27(28)      91(88)                                       ______________________________________                                         *The mixture of diasteromers was separated by reverse phase HPLC at the       ketone (X) stage and carried on individually. The number in parenthesis       refers to the yield of the second diastereomer.                          

The requisite starting materials of formula (VI), phenylhydrazine orsubstituted phenylhydrazines are known or are prepared according toknown methods. A convenient method for preparing the substitutedphenylhydrazines involves the diazotization of the appropriatelysubstituted aniline to give the corresponding diazo derivative. Thelatter compound is then reduced with stannous chloride or sodium sulfiteto give the corresponding phenylhydrazine, see L. F. Fieser and M.Fieser, "Advanced Organic Chemistry," Reinhold Publishing Corporation,New York, 1961, p. 734.

The requisite starting materials of formula (IX) are prepared by severalmethods. At least three of these methods are illustrated in Asselin etal., U.S. Pat. No. 4,057,559.

The above starting materials of formula (V) and formula (VI) are used toprepare the compounds of this invention in the following manner:

The starting material of formula (VI) is condensed with substantiallyone molar equivalent of the starting material of formula (V) to give thecorresponding hydrazone of formula (VII) in which R¹ to R⁶ inclusive areas defined hereinbefore.

Generally speaking, the condensation is performed preferably in an inertatmosphere, for example, nitrogen or argon. Suitable solvents for thecondensation include the lower alkanols such as methanol and ethanol;aromatics such as benzene and toluene; the ethers, such astetrahydrofuran, diethyl ether, dioxane, bis(2-methoxyethyl)-ether andthe like; and the halogenated hydrocarbons, methylene chloride,chloroform and the like. Methanol and ethanol are especially convenientand practical solvents. Times and temperatures for the condensationgenerally range from 5 minutes to five or six days at 0° to 100° C.Convenient time and temperature ranges include 20° C. to the boilingpoint of the mixture and 15 minutes to 130 hours.

The resulting hydrazones (VII) are then cyclized to the tricyclic esterof the acid of formula (I) by the action of a suitable cyclization agentaccording to the conditions of the "Fischer Indole Synthesis," forexample, see B. Robinson, Chem. Rev. 63, 373 (1963).

A variety of cyclization agents are effective for this cyclization, someof the agents suitable for this cyclization include p-toluenesulfonicacid, hydrogen chloride or hydrogen chloride generated from acetylchloride, hydrogen bromide, phosphoric acid, sulfuric acid, aluminumchloride, zinc chloride, hydrogen bromide in acetic acid, borontrifluoride-etherate, trifluoroacetic acid, cationic ion exchange resinssuch as Amberlite IR-120, phenyl or ethyl magnesium bromide and anilinesalts. In other words the usual catalysts employed for the "FischerIndole Synthesis" are efficacious; however, the preferred cyclizationagents are hydrogen chloride or hydrogen chloride generated from acetylchloride.

In practice the isolation of the hydrazone (VII) from the condensationreaction mixture is optional. Accordingly, the cyclization agent isadded either to the above condensation reaction mixture containing thehydrazone, or to the isolated hydrazone optionally dissolved in one ofthe above solvents, whereby the hydrazone then cyclizes to give thecorresponding tricyclic ester of formula (I) in which R¹ to R⁶ inclusiveare as defined hereinbefore.

The cyclization usually proceeds smoothly and rapidly. Convenientreaction times for the cyclization include five minutes to two hours,preferably 30 minutes to one hour. Convenient temperatures include 20°to 200° C., preferably 120° to 180° C.

In practice a most convenient and practical procedure for effecting theabove cyclization comprises evaporating solvent from the condensationreaction mixture containing the hydrazone, and then heating thehydrazone at 120° to 200° C. in one of the aforementioned solutions ofstrong acids.

The starting material of formula (V) may be either a cycloalkanoneaceticacid derivative or its corresponding lower alkyl ester (R⁶ =loweralkyl). Accordingly, when the acid is employed, the above process yieldsthe tricyclic compound identical to the desired compound of formula (I)and when the starting material is lower alkyl ester the above processyields the lower alkyl ester tricyclic compound of formula (I).

The subsequent conversion of the lower alkyl ester tricyclic compound offormula (I) to the corresponding compound of formula (I) is effectedreadily by subjecting the tricyclic compound to hydrolysis. Generallyspeaking, this conversion is most conveniently performed by employing abase as the hydrolyzing agent. The hydrolysis is performed in thepresence of sufficient water optionally under an inert atmosphere,followed by acidification of the reaction mixture to yield the desiredcompound of formula (I). However, the manner of hydrolysis is notintended to be limited to basic hydrolysis since hydrolysis under acidicconditions and other variations, for example, treatment with lithiumiodide in collidine (see L. F. Fieser and M. Fieser, "Reagents forOrganic Synthesis," John Wiley and Sons, Inc., New York, 1967, pp.615-617) are also applicable.

For basic hydrolysis a preferred embodiment involves subjecting thetricyclic ester to the action of a base, for example, sodium orpotassium carbonate, in the presence of sufficient water to effecthydrolysis of the ester. The hydrolysis is performed using a suitablesolvent, for example, methanol or ethanol under a nitrogen atmosphere.

The reaction mixture is maintained at a temperature of from 25° C. tothe reflux temperature until hydrolysis occurs. Usually from 10 minutesto 48 hours is sufficient for this hydrolysis. The reaction is thenrendered acidic with an acid, for example, acetic acid, hydrochloricacid, sulfuric acid and the like, to release the free acid as a solid.

Alternatively, the tricyclic ester is hydrolyzed by subjecting the esterto the action of a hydrolyzing agent which is a strong organic orinorganic acid, for example, trifluoroacetic acid, p-toluenesulfonicacid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid and the like in a suitable solvent at atemperature of at least 60° C. and preferably from 90° C. to the boilingpoint of the mixture until the hydrolysis occurs. Usually from 5 to 48hours are required for this hydrolysis. Suitable solvents include water,acetic acid, aqueous alcohols and the like. If acid hydrolysis is used,the free acid is formed directly. If necessary, the reaction mixture canbe diluted with water to precipitate the product.

The following examples further illustrate this invention.

EXAMPLE 1 4-Ethenyl-1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-aceticAcid (I, R¹ ═--C₂ H₅, R² ═R³ ═R⁴ ═hydrogen, R⁵ ═--C₂ H₅)

(a) Preparation of 2-Ethylcyclohexanone (VIII)

2-Ethylcyclohexanol (1.6 moles, 204 g, 226 ml) was stirred in 3.2 l ofacetone at 0° C. and treated with 8N Jones reagent (prepared from 106.8g of CrO₃ suspended in 92 ml of concentrated sulfuric acid and dilutedto 400 ml with water) until the orange color persisted (˜430 ml).Isopropanol was then added to turn the solution green again after whichit was poured into 2 l of ether. The product was washed with 6×500 ml ofbrine, dried over MgSO₄ and stripped of solvent. Short path distillation(b.p. 80°-85° C. at 25 mm) afforded 184 g (1.46 moles, 91%) of2-ethylcyclohexanone as a colorless oil.

(b) Preparation of 2-Carbomethoxymethyl-2-ethylcyclohexanone (IX)

According to the procedure of E. Negishi and S. Chatterjee, Tet. Lett.,24, 1341 (1983), potassium hydride (417 mmol, 70 ml, ˜6M in mineral oil)was placed under nitrogen in a three-necked flask equipped with amechanical stirrer and was washed three times with petroleum ether (thiswashing can be omitted). Tetrahydrofuran (200 ml, distilled fromsodium/Ph₂ CO) was then added followed by a solution of2-ethylcyclohexanone (VIII) (50 g, 396 mmol) in 200 ml oftetrahydrofuran added as a slow stream over ˜15 minutes. The additionwas followed one minute later by 495 ml of 1M Et₃ B in tetrahydrofuranfollowed 1 hour later by 594 mmol (91 g, 56 ml) of methyl bromoacetate.The yellow suspension was stirred for 2.5 hours, poured into 800 ml ofwater (being careful to decant away from excess KH !) and extracted with4×300 ml of petroleum ether. The combined organic phases were dried oversodium sulfate and concentrated in vacuo. The product was distilledthrough a 6 inches Vigreux column collecting the material boiling at107°-118° C. at 0.8 mm (the two regioisomers from the alkylation). Thismaterial was then purified by flash chromatography to afford 35.33 g(178.2 mmol, 45%) of colorless oil. The desired product is the lowerR_(f) material of the two overlapping spots on thin layer. R_(f) =0.23in 10% ethyl acetate/petroleum ether. About 5-10% of the 2,6regioisiomer can be isolated as the top spot.

(c) Preparation of 6-Carbomethoxymethyl-6-ethyl-2-cyclohexen-1-one (X)

The ketone, 2-carbomethoxymethyl-2-ethylcyclohexanone (IX) (141 mmol, 28g) was stirred in 1.25 l of ethyl acetate (dried over 3A molecularsieves) and treated with 169 mmol (32.5 g) of PhSeCl. The reaction wasstirred under nitrogen for 4 hours then treated with 250 ml of water.The mixture was shaken vigorously in a separatory funnel and the organicphase was returned to the reaction flask. Tetrahydrofuran (550 ml) wasthen added followed by 35 ml of 30% H₂ O₂ (aq.) added dropwise. Thereaction mixture was stirred for one hour then washed with 500 ml ofwater and 500 ml of saturated Na₂ CO₃ (aq.). The product was then driedover MgSO₄ and concentrated in vacuo. Flash chromatography afforded 15.3g (78.0 mmol, 55%) of the product as a pale yellow oil. R_(f) =0.9 in15% ethyl acetate/petroleum ether on TLC.

(d) Preparation of 2-Carbomethoxymethyl-5-ethenyl-2-ethylcyclohexanone(XI, R═--CH═CH₂)

The enone, 6-carbomethoxymethyl-6-ethyl-2-cyclohexen-1-one, prepared bythe process of Step (c) (58.1 mmol, 11.4 g), 5.81 mmol (1.194 g) ofCuBr.Me₂ S and 11.7 ml of Me₂ S were stirred in 176 ml of THF at -40° C.under nitrogen and treated with 58.1 mmol (58.1 ml of 1M solution inTHF) of vinylmagnesium bromide added dropwise over 45 minutes. Thereaction was then quenched with 200 ml of 1M HCl (aq.) and extractedwith 5×100 ml of petroleum ether. Drying (MgSO₄) and flashchromatography afforded 8.96 g (39.9 mmol, 69% pale yellow oil) ofproduct as a mixture of diastereomers. The diastereomers (56:44 ratio)were separated by preparative HPLC on a Prep 500A using a brand ofsilica gel available from Waters Associates, Milford, Ma., anddesignated "more polar isomer" and "less polar isomer."

    ______________________________________                                        NMR-60 MH.sub.z (more polar isomer):                                          No. of Protons                                                                            Type        Chemical Shift/Splitting                              ______________________________________                                        3           CH.sub.2 C .sub.--H.sub.3                                                                 0.85/t J=7                                            9           CH.sub.2 and CH                                                                           1.2-2.3/m                                             2           C .sub.--H.sub.2 COOMe                                                                    2.65/broad s                                          3           OCH.sub.3   3.62/s                                                             ##STR10##  4.8-6.3/m                                             ______________________________________                                    

    ______________________________________                                        NMR-60 MH.sub.z (less polar isomer)                                           No. of Protons                                                                            Type        Chemical Shift/Splitting                              ______________________________________                                        3           CH.sub.2 C .sub.--H.sub.3                                                                 0.55/t J=7                                            11          CH.sub.2 and CH                                                                           1.0-2.7/m                                             3           OCH.sub.3   3.45/s                                                             ##STR11##  4.5-4.9/m                                             1                                                                                          ##STR12##  5.2-5.85/m                                            ______________________________________                                    

(e) Preparation of4-Ethenyl-1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-acetic AcidMethyl Ester

The more polar ketone isomer of2-carbomethoxymethyl-5-ethenyl-2-ethylcyclohexanone (5.084 g, 22.66mmol) and the 2-ethylphenylhydrazine (3.086 g, 22.66 mmol) were heatedat reflux in 97 ml of methanol under nitrogen for 48 hours. The reactionwas then cooled to 0° C., treated with 45.32 mmol (3.56 g, 3.22 ml) ofAcCl and refluxed an additional 45 minutes. Cooling, concentration andflash chromatography afforded 2.772 g (8.52 mmol, 38%) of indole as anorange oil. R_(f) =0.47 in 15% ethyl acetate/petroleum ether on TLC.

    ______________________________________                                        NMR-60 MH.sub.z :                                                             No. of Protons                                                                            Type        Chemical Shift/Splitting                              ______________________________________                                        3           CH.sub.2 C .sub.--H.sub.3                                                                 0.85/t J=7                                            3           ArCH.sub.2 CH.sub.3                                                                       1.4/t J=8                                             6           CH.sub.2    1.55-2.2/m                                            4           CH.sub.2    2.45-3.15/m                                           3           OCH.sub.3   3.7/s                                                 1           C .sub.--HCHCH.sub.2                                                                      3.7/m                                                              ##STR13##  5.0/m                                                 1                                                                                          ##STR14##  5.2/m                                                 1                                                                                          ##STR15##  5.6-6.35/m                                            3           aromatic    6.9-7.5/m                                             1           NH          9.45/broad s                                          ______________________________________                                    

(f) The less polar ketone isomer was taken on to the indole in the sameway to provide the product with the following NMR spectrum:

NMR (CDCl₃ /TMS, 60 MH_(z)): 0.85 (t, 3H, J=7, CH₂ CH₃), 1.35 (t, 3H,J=7, ArCH₂ CH₃), 1.65-2.2 (m, 6H, CH₂), 2.55-3.0 (m, 4H, CH₂), 3.67 (m,1H, CHCH═CH₂), 3.67 (s, 3H, OCH₃), 4.95-6.3 (m, 3H, CH═CH₂), 7.0-7.35(m, 3H, aromatics), 9.3 (broad s, 1H, NH).

(g) Preparation of4-Ethenyl-1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-acetic Acid(XII, R═--CH═CH₂)

The ester (8.44 mmol, 2.7467 g, from the polar ketone, prepared in Step(e), was refluxed in 76 ml of 8:1 v:v methanol/water containing 9.115mmol (1.260 g) of K₂ CO₃. After 24 hours approximately 200 mg of K₂ CO₃were added and the reaction was refluxed another 24 hours. At this pointmost of the solvent was removed in vacuo, the residue was dissolved in20 ml of water and it was acidified to pH=1 with ˜5 ml of 3M HCl (aq.).The product was extracted with 4×25 ml of ether, dried over magnesiumsulfate and concentrated. Flash chromatography afforded 1.71 g (5.49mmol) of orange oil. The product was crystallized from 10 ml of 2.5:1petroleum ether (30-60)/benzene to afford 920 mg (35% yield) of beigecubes which were dried in vacuo (78° C., silica gel) for 8 hours, m.p.144°-147° C.

    ______________________________________                                        NMR-60 MH.sub.z :                                                             No. of Protons                                                                            Type        Chemical Shift/Splitting                              ______________________________________                                        3           CH.sub.2 C .sub.--H.sub.3                                                                 0.9/t J=7                                             3           ArCH.sub.2 C .sub.--H.sub.3                                                               1.35/t J=7                                            6           CH.sub.2    1.7-2.3/m                                             2           ArC .sub.--H.sub.2 CH.sub.3                                                               2.85/q J=7                                            2           C .sub.--H.sub.2 COOH                                                                     2.75/s                                                1           C .sub.--HCC                                                                              3.65/m                                                             ##STR16##  5.0/m                                                 1                                                                                          ##STR17##  5.2/d of d                                            1                                                                                          ##STR18##  5.7-6.3/m                                             3           aromatic    7.0-7.6                                               1           OH          7.9/broad m                                           1           NH          8.9/broad m                                           ______________________________________                                    

IR (KBr): 3490(OH), 3420(NH), 1715(C═O).

(h) The ester (4.078 mmol, 1.3272 g, derived from the less polar ketone,prepared in Step (f)), and K₂ CO₃ (4.404 mmol, 609 mg) were heated atreflux in 37 ml of 8:1 (v:v) MeOH/H₂ O for 24 hours. Another 200 mg ofK₂ CO₃ were then added and the reaction was refluxed an additional 24hours. Most of the MeOH was then removed in vacuo and the residue wasdissolved in 20 ml of water and acidified to pH ˜1 with ˜5 ml of 3M HCl(aq.). The product was extracted with 4×25 ml of petroleum ether, driedover MgSO₄ and concentrated. Flash chromatography afforded 1.15 g (3.702mmol, 91%) of brown oil. The compound was triturated with petroleumether to give 380 mg of tan crystals which were dried at 78° C. for 8hours, m.p. 98°-103° C.

NMR (CDCl₃ /TMS, 60 MH_(z)): 0.9 (t, 3H, J=7, CH₂ CH₃), 1.4 (t,3H, J=7,ArCH₂ CH₃), 1.7-2.3 (m, 6H, CH₂), 2.9 (q, J=7, 2H, ArCH₂ CH₃), 2.7 (s,2H, CH₂ COOH), 3.6 (m, 1H, CHC═C), 4.8-5.2 (m, 2H, C═CH₂), 6.0 (m, 1H,CH═CH₂), 6.8-7.5 (m, 3H, aromatics), 8.9 (broad s, 2H, NH and OH).

IR (KBr): 2300-3700(OH), 3400(NH), 1700(C═O), 1640 and 1610(C═C).

EXAMPLE 2 1,8-Diethyl-2,3,4,9-tetrahydro-4-phenyl-1H-carbazole-1-aceticacid (I, R¹ =R⁵ =--C₂ H₅, R³ =hydrogen, R² and R⁴ joined to form--CH═CH--CH═CH--)

(a) Preparation of 2-Carbomethoxymethyl-2-ethyl-5-phenylcyclohexanone(XI, R=phenyl)

The enone, 6-carbomethoxymethyl-6-ethyl-2-cyclohexen-1-one (X) preparedby the process of Example 1, Step (c) (61.1 mmol, 12.0 g), CuBr.Me₂ S(6.11 mmol, 1.256 g) and Me₂ S (12.3 ml) were stirred in 85 ml of dryTHF at -40° C. under nitrogen and treated with 61.1 mmol (20.4 ml of 3Min THF), of PhMgBr added dropwise over 30 minutes. The reaction was thenquenched with 250 ml of 1M HCl (aq.) and extracted with 4×100 ml ofpetroleum ether. Drying (Na₂ SO₄) and flash chromatography afforded11.87 g (43.3 mmol, 71%) of product. The two diastereomers wereseparated by preparative HPLC on a Prep 500A using a brand of silica gelavailable from Waters Associates, Milford, Ma., affording 4.8 g of eachisomer, designated "less polar isomer" and "more polar isomer."

    ______________________________________                                        NMR-60 MH.sub.z (less polar isomer):                                          No. of Protons                                                                            Type        Chemical Shift/Splitting                              ______________________________________                                        3           CH.sub.2 CH.sub.3                                                                         0.85/t J = 7                                          8           CH.sub.2    1.55-2.25/m                                           2           CH.sub.2 COOMe                                                                             2.5-2.7/m                                                        CH.sub.2 C═O                                                  3           OCH.sub.3   3.7/s                                                 1           ArCH        3.0/m                                                 5           aromatic    7.35/s                                                ______________________________________                                    

IR (less polar isomer): 1745, 1715 C═O.

    ______________________________________                                        NMR-60 MH.sub.z (more polar isomer)                                           No. of Protons                                                                            Type        Chemical Shift/Splitting                              ______________________________________                                        3           CH.sub.2 CH.sub.3                                                                         0.85/t J = 7                                          6           ring CH.sub.2                                                                             1.5-2.3/m                                             4           CH.sub.2 COOMe                                                                            2.6-2.8/m                                                         CH.sub.2 C═O                                                  1           ArCH        3.1/m                                                 3           OCH.sub.3   3.64/s                                                5           aromatics   7.32/s                                                ______________________________________                                    

(b) Preparation of1,8-Diethyl-2,3,4,9-tetrahydro-4-phenyl-1H-carbazole-1-acetic AcidMethyl Ester

The ketone (more polar isomer prepared in Step (a), 16.25 mmol, 4.458 g)and 2-ethylphenylhydrazine (16.25 mmol, 2.213 g) were refluxed in 70 mlof methanol under nitrogen for 48 hours. The reaction was cooled to 0°C., treated with 32.5 mmol (2.55 g, 2.3 ml) of AcCl and refluxed anadditional hour. The solution was then concentrated in vacuo andpurified by flash chromatography to afford 1.92 g (5.23 mmol, 32%) ofyellow oil.

    ______________________________________                                        NMR-60 MH.sub.z :                                                             No. of Protons                                                                            Type        Chemical Shift/Splitting                              ______________________________________                                        3           CH.sub.2 CH.sub.3                                                                         0.8/t, J = 7                                          3           ArCH.sub.2 CH.sub.3                                                                       1.4/t, J = 7                                          6           ring CH.sub.2                                                                 CH.sub.2 CH.sub.3                                                                         1.5-2.1/m                                             2           CH.sub.2 COOMe                                                                            2.65/broad s                                          2           ArCH.sub.2 CH.sub.3                                                                       2.85/q, J = 7                                         3           OCH.sub.3   3.57/s                                                1           PhCH        4.1/broad t, J = 7                                    3           aromatic    6.65-6.45/m                                           5           Ph          7.2/s                                                 1           NH          9.3/broad s                                           ______________________________________                                    

IR: NH 3390 C═O 1730.

(c) The less polar ketone isomer was taken on to the indole in the samemanner to provide the product with the following NMR spectrum:

NMR (CDCl₃ /TMS, 60 MH_(z)): 0.85 (t, J=7, 3H, CH₂ CH₃), 1.35 (t, J=7,3H, ArCH₂ CH₃), 1.55-2.25 (m, 6H, ring CH₂ and CH₂ CH₃), 2.7 (broad s,2H, CH₂ COOMe), 2.85 (q, J=7, 2H, ArCH₂ CH₃), 3.7 (s, 3H, OCH₃), 4.2(broad t, 1H, PhCH), 6.7-7.0 (M, 3H, indole aromatics), 7.25 (s, 5H,Ph), 9.5 (broad s, 1H, NH).

(d) Preparation of1,8-Diethyl-2,3,4,9-tetrahydro-4-phenyl-1H-carbazole-1-acetic Acid (XII,R=phenyl)

The ester (1.964 g, 5.23 mmol), prepared in Step (b), derived from themore polar ketone, and K₂ CO₃ (6.28 mmol, 867 mg) were refluxed undernitrogen in 42 ml of MeOH containing 5.2 ml of water. After 24 hours atreflux and 16 hours at room temperature (the reaction was done by TLCafter the reflux) most of the methanol was removed in vacuo and theresidue was dissolved in 20 ml of water. It was acidified to pH˜1 with3M HCl (aq.) and extracted with 4×25 ml of ether. Drying (MgSO₄) andflash chromatography afforded 1.89 g (5.23 mmol, 100%) of orange oilwhich was crystallized from 10 ml of 2:1 petroleum ether/benzene.Collected were 1.2 g of off-white powder which were shown by elementalanalysis and NMR to be a 1:1 complex with benzene. Drying in vacuo at78° C. (silica gel desiccant) removed the benzene, m.p. 140°-142.5° C.

NMR (CDCl₃ /TMS, 60 MH_(z)): 0.9 (t, J=7, 3H, CH₂ CH₃), 1.34 (t, J=7,3H, ArCH₂ CH₃), 1.6-2.6 (m, 6H, ring CH₂ and aliphatic CH₂ CH₃), 2.9 (s,2H, CH₂ COO), 2.9 (q, J=7, ArCH₂ CH₃), 4.2 (m, 1H, PhCH), 6.7-7.0 (m,3H, indole aromatics), 7.3 (s, 5H, Ph), 8.9 (broad s, 1H, NH).

IR (KBr): 3480(NH), 3600-2500(OH), 3100-2800(CH), 1710(C═O).

(e) The ester, (4.62 mmol, 1.7342 g), prepared in Step (c), derived fromthe less polar ketone, and K₂ CO₃ (5.54 mmol, 766 mg) were refluxedunder nitrogen in 37 ml of MeOH containing 4.63 ml of water. After 24hours at reflux and 16 hours at room temperature, most of the methanolwas removed in vacuo and the residue was dissolved in 20 ml of water.The solution was acidified to pH˜1 with 3M HCl (aq.) and extracted with4×25 ml of ether. Drying (MgSO₄) and flash chromatography afforded 1.69g (4.68 mmol, 100%) of orange oil. About 1.5 g were recrystallized from10 ml of 2:1 petroleum ether/benzene. The product formed as a solid masswhich was ground into a pale yellow powder and washed with petroleumether. Drying at 78° C. in vacuo (silica gel desiccant) gave 850 mg ofpure product, m.p. 118°-121° C.

NMR (CDCl₃ /TMS): 0.93 (t, J=7, 3H, CH₂ CH₃), 1.37 (t, J=7, 3H, ArCH₂CH₃), 1.6-2.5 (M, 6H, ring CH₂ and aliphatic CH₂ CH₃), 2.8 (s, 2H, CH₂COO), 2.9 (q, J=7, 2H, ArCH₂ CH₃), 4.28 (m, 1H, PhCH), 6.9 (m, 3H,indole aromatics), 7.25 (s, 5H, Ph), 9.1 (broad s, 1H, NH).

IR (KBr): 3450(NH), 3600-3100(OH), 1710(C═O).

EXAMPLE 34-(1-Methylethenyl)-1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-aceticAcid (I, R¹ =R⁵ =--C₂ H₅, R² =--CH₃, R³ =hydrogen)

(a) Preparation of2-Carbomethoxymethyl-2-ethyl-5-(1-methylethenyl)-cyclohexanone (XI,R=--C(CH₃)═CH₂)

The enone, 6-carbomethoxymethyl-6-ethyl-2-cyclohexene-1-one, (X),prepared in Example 1, Step (c), (33.12 mmol, 6.50 g), CuBr.Me₂ S (3.312mmol, 681 mg) and Me₂ S (6.63 ml) were stirred in 97.5 ml of dry THF at-40° C. under nitrogen and treated with 49.68 mmol (66.24 ml of 0.75M inTHF, prepared from treating isopropenyl bromide with 1.1 equivalents ofMg) of isopropenylmagnesium bromide added dropwise. The reaction wasquenched with 120 ml of 1M HCl (aq.) and extracted with 4×60 ml ofpetroleum ether. Drying (Na₂ SO₄) and flash chromatography afforded 5.6g (23.53 mmol, 71%) of colorless oil as a mixture of diastereomers. Thediastereomers were separted by preparative HPLC on a Prep 500A using abrand of silica gel available from Waters Associaes, Milford, Ma., toprovide a "less polar isomer" and a "more polar isomer."

Less polar isomer:

NMR (CDCl₃ /TMS, 200 MH_(z)): 0.724 (t, J=7.3, 3H, CH₂ CH₃), 1.2-2.2 (m,6H, CCH₂ CH₂ C, CH₂ CH₃), 1.676 (s, 3H, C═CHCH₃), 2.3-2.9 (m, 5H, CH₂C═O, CH₂ COO, C═CCH₃ CH), 3.584 (s, 3H, OCH₃), 4.6-4.7 (m, 2H, C═CH₂).

IR (neat): 3100 (CH vinyl and aromatic), 3000-2900 (CH aliphatic), 1745(COOMe), 1715 (C═O).

More polar isomer:

NMR (CDCl₃ /TMS, 200 MH_(z)): 0.843 (t, J=7.3, 3H, CH₂ CH₃), 1.2-2.2 (m,6H, CCH₂ CH₂ C, CH₂ CH₃), 1.743 (s, 3H, C═CHCH₃), 2.3-2.9 (m, 5H, CH₂C═O, CH₂ COO, C═CCH₃ CH), 3.626 (s, 3H, OCH₃), 4.75 (M, 2H, C═CH₂).

IR (neat): 3100 (CH vinyl and aromatic), 3000-2900 (CH aliphatic), 1745(COOMe), 1715 (C═O).

(b) Preparation of4-(1-Methylethenyl)-1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-aceticAcid Methyl Ester

The less polar ketone isomer prepared in Step (a), (18.61 mmol, 4.43 g)and 2-ethylphenylhydrazine (24.2 mmol, 3.3 g) were refluxed in 80 ml ofMeOH under nitrogen for 144 hours. The reaction mixture was cooled to 0°C., treated with 37.2 mmol (2.92 g, 2.65 ml) of AcCl and refluxed anadditonal 45 minutes. Concentration in vacuo and flash chromatographyafforded 1.73 g (5.10 mmol, 27%) of orange oil.

Carbazole derived from the less polar ketone:

NMR (CDCl₃ /TMS, 200 MH_(z)): 0.857 (t, 3H, J=7.61, CH₂ CH₃), 1.376 (t,3H, J=7.61, ArCH₂ CH₃), 1.6-2.3 (m, 6H, CHCH₂ CH₂ C, CH₂ CH₃ aliphatic),1.760 (s, 3H, C═CCH₃). 2.6-2.9 (m, 4H, CH₂ COO, ArCH₂ CH₃), 3.67 (m, 1H,C═CCH₃ CH), 3.702 (s, 3H, OCH₃), 4.689 (s, 1H, C═CH₂), 4.863 (s, 1H,C═CH₂), 6.95-7.5 (m, 3H, aromatics), 9.42 (broad s, 1H, NH).

IR (neat): 3410(NH), 3100(vinyl CH), 3000-2900(CH), 1740(C═O).

(c) The more polar ketone isomer prepared in Step (a) was treated in thesame manner to afford 1.71 g (5.04 mmol, 28%) of carbazole:

Carbazole derived from the more polar ketone:

NMR (CDCl₃ /TMS, 200 MH_(z)): 0.849 (t, 3H, J=7.62, CH₂ CH₃), 1.379 (t,3H, J=7.62, ArCH₂ CH₃), 1.6-2.3 (m, 6H, CCH₂ CH₂ C, CCH₂ CH₃ aliphatic),1.731 (s, 3H, C═C CH₃), 2.682 (s, 2H, CH₂ COO), 2.873 (q, 2H, J=7.6,ArCH₂ CH₃), 3.6 (m. 1H, H₂ C═CH₃ CH), 3.681 (s, 3H, OCH₃), 4.73 (s, 1H,C═CH₂), 4.87 (s, 1H, C═CH₂), 6.95-7.5 (m, 3H, aromatics), 9.2 (broad s,1H, NH).

IR (neat): 3410(NH), 3100(vinyl CH), 3000-2900(CH), 1740(C═O).

(d) Preparation of4-(1-Methylethenyl)-1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-aceticAcid (XII, R=--C(CH₃)═CH₂)

The4-(1-methylethenyl)-1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-aceticacid methyl ester (1.72 g, 5.08 mmol), prepared in Step (b), derivedfrom the less polar ketone, and 7.11 mmol of K₂ CO₃ (0.983 g) wererefluxed under nitrogen in 40.6 ml of MeOH containing 5.1 ml of water.After 24 hours, most of the methanol was removed in vacuo and theresidue was dissolved in 15 ml of water. It was acidified to pH˜1 with3M HCl (aq.) and extracted with 4×40 ml of ether. Drying (MgSO₄) andflash chromatography afforded 1.51 g (4.65 mmol, 91%) of yellow oil. Thecompound was recrystallized from 2:1 petroleum ether/benzene to give 988mg of white powder which was dried at 78° C. (high vacuum, phosphorouspentoxide) m.p. 133.5°-135° C.

NMR (CDCl₃ /TMS, 200 MH_(z)): 0.883 (t, 3H, J=7.62, CH₂ CH₃), 1.346 (t,3H, J=7.62, ArCH₂ CH₃), 1.6 (m, 1H) and 1.9-2.1 (m, 5H, CCH₂ CH₂ C, CH₂CH₃), 1.778 (s, 3H C═CCH₃), 2.75 (ABq, 2H, CH₂ COO), 2.841 (q, 2H,J=7.62, ArCH₂ CH₃), 3.587 (broad t, 1H C═CCH₃ CH), 4.648 and 4.867 (2s,2H, C═CH₂), 7.0-7.41 (m, 3H, aromatics), 8.965 (broad s, 1H, NH).

IR (KBr): 3445(NH), 3500-3000(OH), 3070(vinyl H and aryl H),3000-2840(CH), 1708(C═O).

Analysis: Calculated: C(77.49%), H(8.37%), N(4.31%). Found: C(77.62%),H(8.31%), N(4.27%).

(e) The4-(1-methylethenyl)-1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-aceticacid methyl ester (1.71 g, 5.04 mmol), prepared in Step (c), derivedfrom the more polar ketone, and 7.06 mmol of K₂ CO₃ (0.975 g) wererefluxed under nitrogen in 40.3 ml of MeOH containing 5 ml of water.After 24 hours, most of the methanol was removed in vacuo and theresidue was dissolved in 15 ml of water. It was acidified to pH˜1 with3M HCl (aq.) and extracted with 4×40 ml of ether. Drying (MgSO₄) andflash chromatography afforded 1.45 g (4.46 mmol, 88%) of yellow oil. Thecompound was recrystallized from 2:1 petroleum ether/benzene to afford1.11 g of white powder which was dried at 78° C. (high vacuum,phosphorus pentoxide) m.p. 117.5°-119° C.

NMR (CDCl₃ /TMS, 200 MH_(z)): 0.875 (t, 3H, J=7.62, CH₂ CH₃), 1.338 (t,3H, J=7.62, ArCH₂ CH₃), 1.725 (s, 3H, C═CCH₃), 1.8-2.2 (m, 6H, CH₂ CH₃,CCH₂ CH₂ C), 2.762 (s, 2H, CH₂ COO), 2.827 (q, 2H, J=7.62, ArCH₂ CH₃),3.607 (broad t, 1H, C═CCH₃ CH), 4.774 and 4.883 (2S, 2H, H₂ C═C),7.0-7.5 (m, 3H, aromatics), 8.755 (broad s, 1H, NH).

IR (KBr): 3340(NH), 3500-3000(OH), 3050(vinyl H and aryl H),3000-2800(CH), 1700(C═O).

Analysis: Calculated: C(77.49%), H(8.37%), N(4.31%). Found: C(77.65%),H(8.27%), N(4.25).

We claim:
 1. A compound of the formula (I) ##STR19## wherein R¹ is loweralkyl, R², R³ and R⁴ are hydrogen or lower alkyl or R² and R⁴ are joinedtogether to give

    --CH═CH--CH═CH--

and form a benzene ring, R⁵ is hydrogen, lower alkyl or halogen, and thepharmaceutically acceptable salts thereof.
 2. A compound according toclaim 1 wherein R¹ is lower alkyl containing 1 to 6 carbon atoms, R², R³and R⁴ are independently hydrogen or lower alkyl containing 1 to 6carbon atoms or R² and R⁴ are joined together to give

    --CH═CH--CH═CH--

and form a benzene ring, R⁵ is hydrogen, lower alkyl containing 1 to 6carbon atoms or halogen, and the pharmaceutically acceptable saltsthereof.
 3. A compound according to claim 2 wherein R¹ is ethyl, R², R³and R⁴ are hydrogen or R² and R⁴ are joined together to give

    --CH═CH--CH═CH--

and form a benzene ring, R⁵ is hydrogen or ethyl, and thepharmaceutically acceptable salts thereof.
 4. A compound according toclaim 3 designated4-ethenyl-1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid. 5.A compound according to claim 3 designated4-(1-methylethenyl)-1,8-diethyl-2,3,4,9-tetrahydro-1H-carbazole-1-aceticacid.
 6. A compound according to claim 3 designated1,8-diethyl-2,3,4,9-tetrahydro-4-phenyl-1H-carbazole-1-acetic acid.
 7. Apharmaceutical composition comprising a compound of structure (I), or apharmaceutically acceptable salt thereof, as defined in claim 1 and apharmaceutically acceptable carrier.
 8. A method for treatinginflammatory or painful conditions in a mammal which comprises theadministration to said mammal of an effective amount of a compoundselected from those of formula (I), or a pharmaceutically acceptablesalt thereof, as defined in claim 1.